Nude mice given inoculations s.c. of a human squamous carcinoma--HEp3 (1.5 x 10(6) cells/mouse)--developed invasive tumors that produced high levels of urokinase-type plasminogen activator (uPA) and metastasized predictably to the lungs and lymph nodes of the host. To investigate the role of uPA in invasion and metastasis, mice given inoculations of tumor cells were treated daily with s.c. injections of specific, anti-human uPA antibodies (rabbit polyclonal, 150 inhibitory units; mouse monoclonal, 3000 inhibitory units/mouse/day). Control mice received either saline or preimmune rabbit immunoglobulins. A total of approximately 50 mice was studied. The tumors were surgically excised 10 to 17 days postinoculation when weighing 1 to 2 g. Antibody administration was discontinued after tumor excision. Two strategies were used: (a) following the removal of tumors the mice were maintained and observed until respiratory distress, indicative of lung metastasis, was evident; or (b) their lungs were examined for evidence of metastasis on the day of tumor removal. While histological sections of s.c. tumors excised from control mice indicated extensive local invasion, evidence of invasion was absent in most tumors excised from mice in which tumor uPA was inhibited by the antibody (P less than 0.025). The inhibition of local invasion did not, however, lead to a reduced incidence of distant metastasis. Since we found that the presence of HEp3 tumors in mice elicits a pronounced granulocytosis, we propose that this response may facilitate the spread of tumor cells by a mechanism independent of endogenous tumor proteases.